Dr.Watts Antipsychotics Flashcards
General considerations of schizophrenia
Most debilitating of psychotic disorders
onset age 15-20 years old
not split personality
Etiology of schizophrenia
Genetics - neuronal growth, migration of neurons
Environmental - birth complications, infection
Gene- environment interaction - COMT-marijuana
Neurodevelopment - environment interaction
Positive symptoms of schizophrenia
Hallucination, delusion, bizarre behaviors, thoughts disordered (rambling about different things and topics back to back)
Negative symptoms of schizophrenia
Not taking care of yourself, blunted emotions, social withdrawal, poverty in speech (not a lower IQ but cannot put their thoughts together)
Cognitive symptoms of schizophrenia
Decrease in cognitive function involves -D1 receptors and glutamate receptors
Neurotranmitters Hypotheses
Dopamine - FIrst to be developed, but incomplete
Serotonin - based on mechanism of LSD and mescaline
Glutamate - Based on phencyclidine and ketamine
Serotonin hypothesis of schizophrenia
It was found that LSD and mescaline were identified as 5HT receptor agonists which inspired more studies of hallunigenics
Pharmacology found that 5HT receptors are mediators of hallucinations
antagonism and inverse agonism linked to antipsychotic activity
5HT2a receptors modulate dopamine release in cortex, limbic region and striatum
5HT2a receptors modulate glutamate release and NMDA receptors
5HT2c agonists may be beneficial in schizophrenia
Glutamate hypothesis of Schizophrenia
Glutamate is major excitatory neurotransmitter
phencyclidine and ketamine, noncompetitive inhibitors of NMDA receptors exacerbate psychosis and cognition deficit
Dopamine hypothesis of schizophrenia
- D2 receptor antagonists - binding and therapeutics; strong correlation receptor binding affinity vs clinical effectiveness
- Dopaminergic agents exacerbate symptoms of schizophrenia
- Increase D2 receptor density in treated and untreated patients of schizophrenia
- imaging studies - increased DA release and receptor occupancy in patients
D2 receptor antagonists initially increase metabolites in the CNS later decrease metabolites in CNS
Determining binding affinity
This is the intermolecular force between ligan and receptor
Kd/Ki: estimated concentration at which 1/2 of the receptors are occupied (lower value means more affinity
Saturation binding experiments and competition binding experiments
Binding affinity vs Clinical dose (D1,D2)
the study shows that for D1 receptor there is no correlation between binding affinity and clinical dose
For D2 receptors there was a perfect correlation between binding affinity and clinical dose which suggests the ability of antipsychotic drugs to bind to the d2 receptor is predictive based off its concentration dose
Actions of D2 antagonists in the CNS
Basal ganglia: by blocking dopamine here we see parkinsons like symptoms like shaking
Mesolimbic: where we want to target for schizophrenia
Mesocortical: if we block dopamine here we might enhance the cognitive deficit seen in schizophrenia because action here is already low in these patients
Hypothalamus and endocrine systems: D2 receptor blockade in endocrine system
Medulla: D2 antagonists here will work at the chemoreceptor trigger zone and block the feeling of nausea and vomiting
Extrapyramidal symptoms
Extrapyramidal symptoms
- occurs early, days/weeks, reversible
symptoms: dytonia, pseudoparkinsonism, tremor, akathisia
Drug therapy for EPS: Benzotropine, trihexyphenidyl, Diphenhydramine, amantadine
when drug-induced movements disorders occur, what target is responsible, which drugs
are likely to cause them, and how or if the movement disorders can be treated.
target responsible would be dopamine in basal ganglia
treatment includes : amantadine, diphenhydramine, trihexyphenidyl, and benzotropine
Tardive Dyskinesia
movement disorder caused by anticholenergics
occurs late, months to a year, irreversible
symptoms: mouth, irregular purposelessness, axial hyperkinesia, athetoid
Not super clear how this disorder happens but some studies say that its due to increased senzitivity of dopamine receptors. Being blocked constantly and cell overcompensates for that loss and the receptors become sensitive.
Treatment: prevention (use least risky agent at the lowest dose possible (change to newer drug or eliminate anticholinergic or VMAT inhibitor) and monitor (abnormal involuntary movement scale) check rating every 6 months
